The major goals of this project are to prevent the loss of function that occurs in skeletal muscle during disuse and to increase the rate of recovery of muscle function upon reloading. Disuse atrophy is a major problem in the elderly and is one of the major hurdles that must be overcome for extended human exposure to microgravity (i.e. long periods in the space environment). We will take advantage of the ability of recombinant adeno-associated virus (AAV) to effect gene transfer in skeletal muscle. This work will lay the foundations for gene transfer therapies to reserve muscle function during periods of unloading and to increase the rate and extent of recovery upon reloading. Two major aims will be addressed: 1) preventing disuse atrophy; and 2) increasing the rate of functional recovery upon reloading. The first aim will dissect the signaling pathways that drive disuse atrophy and will address the hypothesis that both apoptotic and growth pathways are 'affected. The pivotal role of focal adhesion kinase in this process will be examined. The second aim addresses the hypothesis that following a period of disuse, the action of IGF-I will enhance the rate of recovery. Additionally, we will test the hypothesis that a large amount of the damage upon reloading is due to oxygen free radical injury. The experiments delineated under each aim will provide mechanistic insights into the multi-faceted problem of disuse atrophy. In addition, the experiments will provide the foundations for future gene transfer approaches aimed at ameliorating functional loss concomitant with disuse, for human exploration of space, and for a healthier life for the elderly on earth, we must understand and design measures to prevent disuse atrophy of skeletal muscle.